Pyrroloindoles, pyridoindoles and azepinoindoles as 5-ht2c agonists

ABSTRACT

A chemical compound of formula (I), wherein n is 1, 2 or 3; R1 and R2 are independently selected from hydrogen and alkyl; R3 is alkyl; R4 to R7 are independently selected from hydrogen, halogen, hydroxy, alkyl, aryl, alkoxy, aryloxy, alkylthio, arylthio, alkylsulfoxyl, alkylsulfonyl, arylsulfoxyl, arylsulfonyl, amino, monoalkylamino, dialkylamino, nitro, cyano, carboxaldehyde, alkylcarbonyl, arylcarbonyl, aminocarbonyl, monoalkylaminocarbonyl, dialkylaminocarbonyl, alkoxycarbonylamino, aminocarbonyloxy, monoalkylaminocarbonyloxy, dialkylaminocarbonyloxy, monoalkylaminocarbonylamino and dialkylaminocarbonylamino, or R5 and R6 together form a carbocyclic or heterocyclic ring, and pharmaceutically acceptable salts and prodrugs thereof, and the use thereof in therapy, particularly for the treatment of disorders of the central nervous system; damage to the central nervous system; cardiovascular disorders; gastrointestinal disorders, diabetes insipidus, and sleep apnea, and particularly for the treatment of obesity

This application is a 371 PCT/GB99/02884 filed on Sep. 1, 1999.

The present invention relates to pyrroloindole, pyridoindole andazepinoindole derivatives, to processes and intermediates for theirpreparation, to pharmaceutical compositions containing them and to theirmedicinal use. The active compounds of the present invention are usefulin treating obesity and other disorders.

It has been recognised that obesity is a disease process influenced byenvironmental factors in which the traditional weight loss methods ofdieting and exercise need to be supplemented by therapeutic products (S.Parker, “Obesity: Trends and Treatments”, Scrip Reports, PJBPublications Ltd, 1996).

Whether someone is classified as overweight or obese is generallydetermined on the basis of their body mass index (BMI) which iscalculated by dividing body weight (kg) by height squared (m²). Thus,the units of BMI are kg/m² and it is possible to calculate the BMI rangeassociated with minimum mortality in each decade of life. Overweight isdefined as a BMI in the range 25-30 kg/m², and obesity as a BMI greaterthan 30 kg/m². There are problems with this definition in that it doesnot take into account the proportion of body mass that is muscle inrelation to fat (adipose tissue). To account for this, obesity can alsobe defined on the basis of body fat content: greater than 25% and 30% inmales and females, respectively.

As the BMI increases there is an increased risk of death from a varietyof causes that is independent of other risk factors. The most commondiseases with obesity are cardiovascular disease (particularlyhypertension), diabetes (obesity aggravates the development ofdiabetes), gall bladder disease (particularly cancer) and diseases ofreproduction. Research has shown that even a modest reduction in bodyweight can correspond to a significant reduction in the risk ofdeveloping coronary heart disease.

Compounds marketed as anti-obesity agents include Orlistat (Reductil®)and Sibutramine. Orlistat (a lipase inhibitor) inhibits fat absorptiondirectly and tends to produce a high incidence of unpleasant (thoughrelatively harmless) side-effects such as diarrhoea. Sibutramine (amixed 5-HT/noradrenaline reuptake inhibitor) can increase blood pressureand heart rate in some patients. The serotonin releaser/reuptakeinhibitors fenfluramine (Pondimin®) and dexfenfluramine (Redux™) havebeen reported to decrease food intake and body weight over a prolongedperiod (greater than 6 months). However, both products were withdrawnafter reports of preliminary evidence of heart valve abnormalitiesassociated with their use. There is therefore a need for the developmentof a safer anti-obesity agent.

The non-selective 5-HT_(2C) receptor agonists/partial agonistsm-chlorophenylpiperazine (mCPP) and trifluoromethylphenylpiperazine(TFMPP) have been shown to reduce food intake in rats (G. A. Kennett andG. Curzon, Psychopharmacol., 1988, 96, 93-100; G. A. Kennett, C. T.Dourish and G. Curzon, Eur. J. Pharmacol., 1987, 141, 429-435) and toaccelerate the appearance of the behavioural satiety sequence (S. J.Kitchener and C. T. Dourish, Psychopharmacol., 1994, 113, 369-377).Recent findings from studies with mCPP in normal human volunteers andobese subjects have also shown decreases in food intake. Thus, a singledose of mCPP decreased food intake in female volunteers (A. E. S. Walshet al., Psychopharmacol., 1994, 116, 120-122) and decreased the appetiteand body weight of obese male and female subjects during subchronictreatment for a 14 day period (P. A. Sargeant et al., Psychopharmacol.,1997, 133, 309-312). The anorectic action of mCPP is absent in 5-HT_(2C)receptor knockout mutant mice (L. H. Tecott et al., Nature, 1995, 374,542-546) and is antagonised by the 5-HT_(2C) receptor antagonistSB-242084 in rats (G. A. Kennett et al., Neuropharmacol., 1997, 36,609-620). It seems therefore that mCPP decreases food intake via anagonist action at the 5-HT_(2C) receptor.

Other compounds which have been proposed as 5-HT_(2C) receptor agonistsfor use in the treatment of obesity include the substituted 1-aminoethylindoles disclosed in EP-A-0655440. CA-2132887 and CA-2153937 disclosethat tricyclic 1-aminoethylpyrrole derivatives and tricyclic1-aminoethyl pyrazole derivatives bind to 5-HT_(2C) receptors and may beused in the treatment of obesity. WO-A-98/30548 disclosesaminoalkylindazole compounds as 5-HT_(2C) agonists for the treatment ofCNS diseases and appetite regulation disorders.2-(2,3-Dihydro-1H-pyrrolo[1,2-a]indol-9-yl)ethylamine is disclosed inJ.Med.Chem., 1965, 8, 700. The preparation of pyrido[1,2-a]indoles forthe treatment of cerebrovascular disorders is disclosed in EP-A-0252643and EP-A-0167901. The preparation of10-[(acylamino)ethyl]tetrahydropyrido[1,2a]indoles as anti-ischemicagents is disclosed in EP-A-0279125.

It is an object of this invention to provide selective, directly acting5HT₂ receptor ligands for use in therapy and particularly for use asanti-obesity agents. It is a further object of this invention to providedirectly acting ligands selective for 5-HT_(2B) and/or 5-HT_(2C)receptors, for use in therapy and particularly for use as anti-obesityagents. It is a further object of this invention to provide selective,directly acting 5-HT_(2C) receptor ligands, preferably 5-HT_(2C)receptor agonists, for use in therapy and particularly for use asanti-obesity agents.

According to the present invention there is provided a chemical compoundof formula (I):

wherein:

n is 1,2 or 3;

R₁ and R₂ are independently selected from hydrogen and alkyl;

R₃ is alkyl;

R₄ to R₇ are independently selected from hydrogen, halogen, hydroxy,alkyl, aryl, alkoxy, aryloxy, alkylthio, arylthio, alkylsulfoxyl,alkylsulfonyl, arylsulfoxyl, arylsulfonyl, amino, monoalkylamino,dialkylamino, nitro, cyano, carboxaldehyde, alkylcarbonyl, arylcarbonyl,aminocarbonyl, monoalkylaminocarbonyl, dialkylaminocarbonyl,alkoxycarbonylamino, aminocarbonyloxy, monoalkylaminocarbonyloxy,dialkylaminocarbonyloxy, monoalkylaminocarbonylamino anddialkylaminocarbonylamino, or R₅ and R₆ together form a carbocyclic orheterocyclic ring,

and pharmaceutically acceptable salts and prodrugs thereof.

As used herein, the term “alkyl” means a branched or unbranched, cyclicor acyclic, saturated or unsaturated (e.g. alkenyl or alkynyl)hydrocarbyl radical. Where cyclic, the alkyl group is preferably C₃ toC₁₂, more preferably C₅ to C₁₀, more preferably C₅, C₆ or C₇. Whereacyclic, the alkyl group is preferably C₁ to C₁₀, more preferably C₁ toC₆, more preferably methyl, ethyl, propyl (n-propyl or isopropyl) orbutyl (n-butyl, isobutyl or tertiary-butyl), more preferably methyl.

As used herein, the term “lower alkyl” means methyl, ethyl, propyl(n-propyl or isopropyl) or butyl (n-butyl, isobutyl or tertiary-butyl).

As used herein, the term “aryl” means an aromatic group, such as phenylor naphthyl, or a heteroaromatic group containing one or more,preferably one, heteratom, such as pyridyl, pyrrolyl, furanyl andthienyl.

The alkyl and aryl groups may be substituted or unsubstituted. Wheresubstituted, there will generally be 1 to 3 substituents present,preferably 1 substituent. Substituents may include:

carbon-containing groups such as

alkyl,

aryl,

arylalkyl (e.g. substituted and unsubstituted phenyl, substituted

and unsubstituted benzyl);

halogen atoms and halogen-containing groups such as

haloalkyl (e.g. trifluoromethyl);

oxygen-containing groups such as

alcohols (e.g. hydroxy, hydroxyalkyl, aryl(hydroxy)alkyl),

ethers (e.g. alkoxy, aryloxy, alkoxyalkyl, aryloxyalkyl),

aldehydes (e.g. carboxaldehyde),

ketones (e.g. alkylcarbonyl, alkylcarbonylalkyl, arylcarbonyl,arylalkylcarbonyl, arylcarbonylalkyl),

acids (e.g. carboxy, carboxyalkyl),

acid derivatives such as esters (e.g. alkoxycarbonyl,alkoxycarbonylalkyl, alkylcarbonyloxy, alkylcarbonyloxyalkyl),

amides (e.g. aminocarbonyl, mono- or di-alkylaminocarbonyl,aminocarbonylalkyl, mono- or di-alkylaminocarbonylalkyl,arylaminocarbonyl),

carbamates (e.g. alkoxycarbonylamino, aryloxycarbonylamino,aminocarbonyloxy, mono- or di-alkylaminocarbonyloxy,arylaminocarbonyloxy)

and ureas (e.g. mono- or di-alkylaminocarbonylamino orarylaminocarbonylamino);

nitrogen-containing groups such as

amines (e.g. amino, mono- or di-alkylamino, aminoalkyl, mono- ordi-alkylaminoalkyl),

azides,

nitriles (e.g. cyano, cyanoalkyl),

nitro;

sulfur-containing groups such as

thiols, thioethers, sulfoxides and sulfones (e.g. alkylthio,alkylsulfinyl, alkylsulfonyl, alkylthioalkyl, alkylsulfinylalkyl,alkylsulfonylallyl, arylthio, arylsulfinyl, arylsulfonyl, arylthioalkyl,arylsulfinylalkyl, arylsulfonylalkyl);

and heterocyclic groups containing one or more, preferably one,heteroatom, (e.g. thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl,thiazolyl, isothiazolyl, oxazolyl, oxadiazolyl, thiadiazolyl,aziridinyl, azetidinyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl,imidazolinyl, pyrazolidinyl, tetrahydrofuranyl, pyranyl, pyronyl,pyridyl, pyrazinyl, pyridazinyl, piperidyl, hexahydroazepinyl,piperazinyl, morpholinyl, thianaphthyl, benzofuranyl, isobenzofuranyl,indolyl, oxyindolyl, isoindolyl, indazolyl, indolinyl, 7-azaindolyl,benzopyranyl, coumarinyl, isocoumarinyl, quinolinyl, isoquinolinyl,naphthridinyl, cinnolinyl, quinazolinyl, pyridopyridyl, benzoxazinyl,quinoxalinyl, chromenyl, chromanyl, isochromanyl, phthalazinyl andcarbolinyl).

As used herein, the term “alkoxy” means alkyl-O- and “alkoyl” meansalkyl-CO-. Alkoxy substituent groups or alkoxy-containing substituentgroups may be substituted by one or more alkyl groups.

As used herein, the term “halogen” means a fluorine, chlorine, bromineor iodine radical, preferably a fluorine, chlorine or bromine radical.

As used herein the term “prodrug” means any pharmaceutically acceptableprodrug of the compound of formula (I).

As used herein, the term “pharmaceutically acceptable salt” means anypharmaceutically acceptable salt of the compound of formula (I). Saltsmay be prepared from pharmaceutically acceptable non-toxic acids andbases including inorganic and organic acids and bases. Such acidsinclude acetic, benzenesulfonic, benzoic, camphorsulfonic, citric,ethenesulfonic, dichloroacetic, formic, fumaric, gluconic, glutamic,hippuric, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic,mandelic, methanesulfonic, mucic, nitric, oxalic, pamoic, pantothenic,phosphoric, succinic, sulfiric, tartaric, oxalic, p-toluenesulfonic andthe like. Particularly preferred are fumaric, hydrochloric, hydrobromic,phosphoric, succinic, sulfuric and methanesulfonic acids. Acceptablebase salts include alkali metal (e.g. sodium, potassium), alkaline earthmetal (e.g. calcium, magnesium) and aluminium salts.

In a preferred embodiment, the compounds of formula (I) are selectedfrom compounds in which n is 1.

Preferably, the compounds of formula (I) are selected from compounds inwhich R₁ is the same as R₂. Preferably, R₁ and R₂ are both hydrogen. Inan embodiment of the invention, R₁ is hydrogen and R₂ is alkyl(preferably lower alkyl and more preferably methyl) optionallysubstituted by an aryl (preferably a substituted or unsubstituted phenylor thienyl group) or by a cycloalkyl group (preferably saturated andpreferably selected from a C₃, C₄, C₅, C₆ and C₇ cycloalkyl group).

Preferably, the compounds of formula (I) are selected from compounds inwhich R₃ is lower alkyl, preferably methyl or ethyl, preferably methyl.The carbon atom to which R₃ is bound is an asymmetric carbon atom. It ispreferred that this asymmetric carbon atom is in the (S)-configuration,wherein the stereochemical assignment is defined with respect to acompound wherein R₃ is an unsubstituted alkyl group.

R₄ to R₇ are independently selected from hydrogen, halogen, hydroxy,alkyl (including cycloalkyl, halo-alkyl (such as trifluoromethyl) andarylalkyl), aryl, alkoxy (including arylalkoxy), aryloxy, alkylthio,arylthio, alkylsulfoxyl, alkylsulfonyl, arylsulfoxyl, arylsulfonyl,amino, monoalkylamino, dialkylamino, nitro, cyano, carboxaldehyde,alkylcarbonyl, arylcarbonyl, aminocarbonyl, monoalkylaminocarbonyl,dialkylaminocarbonyl, alkoxycarbonylamino, aminocarbonyloxy,monoalkylaminocarbonyloxy, dialkylaminocarbonyloxy,monoalkylaminocarbonylamino and dialkylaminocarbonylamino, or R₅ and R₆together form a carbocyclic or heterocyclic ring.

In an embodiment of the invention, R₄ to R₇ are independently selectedfrom hydrogen, halogen, hydroxy, alkyl (including cycloalkyl, halo-alkyl(such as trifluoromethyl) and arylalkyl), aryl, alkoxy (includingarylalkoxy), aryloxy, alkylthio, alkylsulfoxyl and alkylsulfonyl.

It is preferred that R₄ is selected from hydrogen and halogen,preferably hydrogen.

It is preferred that R₅ is selected from a substituent group other thanhydrogen, and preferably from halogen, alkyl, alkoxy, alkylthio,alkylsulfonyl, monoalkylamino and dialkylamino, and more preferably fromhalogen (preferably fluoro, chloro and bromo), alkyl (preferably loweralkyl and preferably trifluoromethyl), alkoxy (preferably lower alkoxy)and alkylthio (preferably lower alkylthio).

It is preferred that R₆ is selected from halogen (preferably fluoro andchloro) and hydrogen. In an embodiment of the invention, R₆ is asubstituent group other than hydrogen.

It is preferred that R₇ is hydrogen.

In an embodiment of the invention, two or three of R₄, R₅, R₆ and R₇,preferably two or three of R₄, R₆ and R₇, and preferably at least R₄ andR₇, are hydrogen.

In an embodiment of the invention, R₅ and R₆ may together form acarbocyclic or heterocyclic ring, preferably a heterocyclic ring. Thering may be a 4, 5, 6 or 7-membered ring, preferably a 5- or 6-memberedring, and preferably a 5-membered ring. The ring may be aliphatic oraromatic, preferably aliphatic. Where heterocyclic, the ring may contain1, 2 or 3 heteroatoms, preferably 1 or 2 heteroatoms. The heteroatomsmay be selected from O, S or N. The ring may be substituted orunsubstituted as defined above for “alkyl” groups and “aryl” groups. Ina preferred embodiment, R₅ and R₆ together form a methylenedioxy groupwhich forms a ring with the adjacent carbon atoms of the phenyl group towhich it is bound. As used herein, the term “carbocyclic ring” means aring in which each of the ring atoms are carbon atoms.

In a preferred embodiment, the compounds of formula (I) are selectedfrom 1-(7-chloro-2,3-dihydro-1H-pyrrolo[1,2-a]indol-9-yl)-2-propylamine,1-(6,7-difluoro-2,3-dihydro-1H-pyrrolo[1,2-a]indol-9-yl)-2-propylamine,1-(7-bromo-2,3-dihydro-1H-pyrrolo[1,2-a]indol-9-yl)-2-propylamine,1-(7-methoxy-2,3-dihydro-1H-pyrrolo[1,2-a]indol-9-yl)-2-propylamine and1-(7-methylthio-2,3-dihydro-1H-pyrrolo[1,2-a]indol-9-yl)-2-propylamine,and particularly the (S)-enantiomers thereof. Where the compounds offormula (I) are in salt form, the fumarate salts are preferred.

The compounds of the invention may contain one or more asymmetric carbonatoms, so that the compounds can exist in different stereoisomericforms. The compounds can be, for example, racemates or optically activeforms. The optically active forms can be obtained by resolution of theracemates or by asymmetric synthesis.

In a preferred embodiment of the invention, a compound of formula (I) isin the form of its (S)-enantiomer, substantially free of its(R)-enantiomer. As used herein, the term “substantially free of its(R)-enantiomer” means that a composition comprising a compound offormula (I) contains a greater proportion of the (S)-enantiomer of thecompound of formula (I) in relation to the (R)-enantiomer of thecompound of formula (I). In a preferred embodiment of the presentinvention, the term “substantially free of its (R)-enantiomer”, as usedherein, means that the composition contains at least 90% by weight ofthe (S)-enantiomer and 10% by weight or less of the (R)-enantiomer. In afurther preferred embodiment, the term “substantially free of its(R)-enantiomer” means that the composition contains at least 99% byweight of the (S)-enantiomer and 1% or less of the (R)-enantiomer. Inanother preferred embodiment, the term “substantially free of its(R)-enantiomer” means that the composition contains 100% by weight ofthe (S)-enantiomer. The above percentages are based on the total amountof a compound of formula (I) present in the composition.

According to a further aspect of the invention, there is provided acompound of formula (I) for use in therapy.

The compounds of formula (I) may be used in the treatment (includingprophylactic treatment) of disorders associated with 5-HT₂ receptorfunction. The compounds may act as receptor agonists or antagonists.Preferably, the compounds may be used in the treatment (includingprophylactic treatment) of disorders associated with 5-HT_(2B) and/or5-HT_(2C) receptor function. Preferably, the compounds may be used inthe treatment (including prophylactic treatment) of disorders where a5-HT_(2C) receptor agonist is required.

The compounds of formula (I) may be used in the treatment or preventionof central nervous disorders such as depression, atypical depression,bipolar disorders, anxiety disorders, obsessive-compulsive disorders,social phobias or panic states, sleep disorders, sexual dysfunction,psychoses, schizophrenia, migraine and other conditions associated withcephalic pain or other pain, raised intracranial pressure, epilepsy,personality disorders, age-related behavioural disorders, behaviouraldisorders associated with dementia, organic mental disorders, mentaldisorders in childhood, aggressivity, age-related memory disorders,chronic fatigue syndrome, drug and alcohol addiction, obesity, bulimia,anorexia nervosa or premenstrual tension; damage of the central nervoussystem such as by trauma, stroke, neurodegenerative diseases or toxic orinfective CNS diseases such as encephalitis or meningitis;cardiovascular disorders such as thrombosis; gastrointestinal disorderssuch as dysfunction of gastrointestinal motility; diabetes insipidus;and sleep apnea.

According to a further aspect of the invention, there is provided use ofa compound of formula (I) in the manufacture of a medicament for thetreatment (including prophylaxis) of the above-mentioned disorders. In apreferred embodiment, there is provided use of a compound of formula (I)in the manufacture of a medicament for the treatment (includingprophylaxis) of obesity.

According to a further aspect of the invention, there is provided amethod of treatment (including prophylaxis) of a disorder selected fromthe group consisting of the above-mentioned disorders comprisingadministering to a patient in need of such treatment an effective doseof a compound of formula (I). In a preferred embodiment, there isprovided a method of treatment (including prophylaxis) of obesity.

According to a further aspect of the invention, there is provided apharmaceutical composition comprising a compound of formula (I) incombination with a pharmaceutically acceptable carrier or excipient anda method of making such a composition comprising combining a compound offormula (I) with a pharmaceutically acceptable carrier or excipient.

According to a further aspect of the invention, there is provided amethod of preparing a compound of formula (I).

Compounds of the invention may be prepared according to Reaction Scheme1 below. R₁ to R₇ are as previously defined. The aldehyde (III) may beprepared by reaction of indole (II) with for example, phosphorusoxychloride in dimethylformamide. The chloride (IV) can be formed fromthe aldehyde (III) by reaction with a suitable bromo-chloro-alkane,iodo-chloro-alkane or chloro-alkane-sulfonate in the presence of a basesuch as potassium hydroxide in a solvent such as dimethyl sulfoxide.Formation of the iodide (V) may be achieved by reaction of the chloride(IV) with an iodide salt such as sodium iodide in a solvent such asacetonitrile. The aldehyde (VI) may be formed by reaction of the iodide(V) with a trialkyltin hydride in the presence of a reagent such as1,1′-azobis(cyclohexanecarbonitrile) or azobisisobutyronitrile in asolvent such as toluene. The nitroalkene (VII) may be obtained byreaction of the aldehyde (VI) with a nitroalkane. Compounds of formula(I) can be formed in the reaction of the nitroalkene (VII) with areducing agent such as lithium aluminium hydride in an ethereal solvent.

The compounds of formula (I) (R₁ and/or R₂=alkyl) may be prepared fromcompounds of formula (I) (R₁=R₂=H) by standard methods such as reductivealkylation with an appropriate aldehyde or ketone in the presence of areducing agent such as sodium triacetoxyborohydride, formic acid orsodium cyanoborohydride.

If, in any of the processes mentioned herein, the substituent group R₄,R₅, R₆ or R₇ is other than the one required, the substituent group maybe converted to the desired substituent by known methods. Thesubstituents R₄, R₅, R₆ or R₇ may also need protecting against theconditions under which the reaction is carried out. In such a case, theprotecting group may be removed after the reaction has been completed.

The processes described above may be carried out to give a compound ofthe invention in the form of a free base or as an acid addition salt. Ifthe compound of the invention is obtained as an acid addition salt, thefree base can be obtained by basifying a solution of the acid additionsalt. Conversely, if the product of the process is a free base, an acidaddition salt, particularly a pharmaceutically acceptable acid additionsalt, may be obtained by dissolving the free base in a suitable organicsolvent and treating the solution with an acid, in accordance withconventional procedures for preparing acid addition salts from basiccompounds.

The compositions of the present invention may be formulated in aconventional manner using one or more pharmaceutically acceptablecarriers. Thus, the active compounds of the invention may be formulatedfor oral, buccal, intranasal, parenteral (e.g., intravenous,intramuscular or subcutaneous) transdermal or rectal administration orin a form suitable for administration by inhalation or insufflation.

For oral administration, the pharmaceutical compositions may take theform of, for example, tablets or capsules prepared by conventional meanswith pharmaceutically acceptable excipients such as binding agents (e.g.pregelatinised maize starch, polyvinylpyrrolidone orhydroxypropylmethylcellulose); fillers (e.g. lactose, microcrystallinecellulose or calcium phosphate); lubricants (e.g. magnesium stearate,talc or silica); disintegrants (e.g. potato starch or sodium starchglycollate); or wetting agents (e.g. sodium lauryl sulfate). The tabletsmay be coated by methods well known in the art. Liquid preparations fororal administration may take the form of, for example, solutions, syrupsor suspensions, or they may be presented as a dry product forconstitution with water or other suitable vehicle before use. Suchliquid preparations may be prepared by conventional means withpharmaceutically acceptable additives such as suspending agents (e.g.sorbitol syrup, methyl cellulose or hydrogenated edible fats);emulsifying agents (e.g. lecithin or acacia); non-aqueous vehicles (e.g.almond oil, oily esters or ethyl alcohol); and preservatives (e.g.methyl or propyl p-hydroxybenzoates or sorbic acid).

For buccal administration the composition may take the form of tabletsor lozenges formulated in conventional manner.

The active compounds of the invention may be formulated for parenteraladministration by injection, including using conventionalcatheterization techniques or infusion. Formulations for injection maybe presented in unit dosage form e.g. in ampoules or in multi-dosecontainers, with an added preservative. The compositions may take suchforms as suspensions, solutions or emulsions in oily or aqueousvehicles, and may contain formulating agents such as suspending,stabilizing and/or dispersing agents.

Alternatively, the active ingredient may be in powder form forreconstitution with a suitable vehicle, e.g. sterile pyrogen-free water,before use.

The active compounds of the invention may also be formulated in rectalcompositions such as suppositories or retention enemas, e.g., containingconventional suppository bases such as cocoa butter or other glycerides.

For intranasal administration or administration by inhalation, theactive compounds of the invention are conveniently delivered in the formof a solution or suspension from a pump spray container that is squeezedor pumped by the patient or as an aerosol spray presentation from apressurized container or a nebulizer, with the use of a suitablepropellant, e.g. dichlorodifluoromethane, trichlorofluoromethane,dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In thecase of a pressurized aerosol, the dosage unit may be determined byproviding a valve to deliver a metered amount. The pressurized containeror nebulizer may contain a solution or suspension of the activecompound. Capsules and cartridges (made, for example, from gelatin) foruse in an inhaler or insufflator may be formulated containing a powdermix of a compound of the invention and a suitable powder base such aslactose or starch.

A proposed dose of the active compounds of the invention for oral,parenteral or buccal administration to the average adult human for thetreatment of the conditions referred to above (e.g., obesity) is 0.1 to500 mg of the active ingredient per unit dose which could beadministered, for example, 1 to 4 times per day.

The invention will now be described in detail with reference to thefollowing examples. It will be appreciated that the invention isdescribed by way of example only and modification of detail may be madewithout departing from the scope of the invention.

Experimental

Assay Procedures

1. Binding to Serotonin Receptors

The binding of compounds of formula (I) to serotonin receptors wasdetermined in vitro by standard methods. The preparations wereinvestigated in accordance with the assays given hereinafter.

Method (a): For the binding to the 5-HT_(2C) receptor the 5-HT_(2C)receptors were radiolabeled with [³H]-5-HT. The affinity of thecompounds for 5-HT_(2C) receptors in a CHO cell line was determinedaccording to the procedure of D. Hoyer, G. Engel and H. O. Kalkman,European J. Pharmacol., 1985, 118, 13-23.

Method (b): For the binding to the 5-HT_(2B) receptor the 5-HT_(2B)receptors were radiolabeled with [³H]-5-HT. The affinity of thecompounds for human 5-HT_(2B) receptors in a CHO cell line wasdetermined according to the procedure of K. Schmuck, C. Ullmer, P.Engels and H. Lubbert, FEBS Lett., 1994, 342, 85-90.

Method (c): For the binding to the 5-HT_(2A) receptor the 5-HT_(2A)receptors were radiolabeled with [¹²⁵I]-DOI. The affinity of thecompounds for 5-HT_(2A) receptors in a CHO cell line was determinedaccording to the procedure of D. J. McKenna and S. J. Peroutka, J.Neurosci., 1989, 9, 3482-90.

The thus determined activity of compounds of formula (I) is shown inTable 1.

TABLE 1 Compound K_(i) (2C) nM K_(i) (2B) nM K_(i) (2A) nM Example 1 110229 457 Example 2 97 102 257 Example 3 118 220 151 Example 5 81 122 448Example 11 84 115 316

2. Functional Activity

The functional activity of compounds of formula (I) was assayed using aFluorimetric Imaging Plate reader (FLIPR). CHO cells expressing thehuman 5-HT_(2C) or human 5-HT_(2A) receptors were counted and platedinto standard 96 well microtitre plates on the day before testing togive a confluent monolayer. The cells were then dye loaded with thecalcium sensitive dye, Fluo-3-AM. Unincorporated dye was removed usingan automated cell washer to leave a total volume of 100 μL/well of assaybuffer (Hanks balanced salt solution containing 20 mM Hepes and 2.5 mMprobenecid). The drug (dissolved in 50 μL of the assay buffer) was addedat a rate of 70 μL/sec to each well of the FLIPR 96 well plate duringfluorescence measurements. The measurements were taken at 1 secintervals and the maximum fluorescent signal was measured (approx 10-15secs after drug addition) and compared with the response produced by 10μM 5-HT (defined as 100%) to which it was expressed as a percentageresponse (relative efficacy). Dose response curves were constructedusing Graphpad Prism (Graph Software Inc.).

The thus determined activity of compounds of formula (I) is shown inTable 2.

TABLE 2 h5-HT_(2A) h5-HT_(2c) Relative Relative Compound EC₅₀ (nM)Efficacy (%) EC₅₀ (nM) Efficacy (%) Example 1 3236 33 96 68 Example2 >1000 12 147 38 Example 3 636 22 32 63 Example 5 4020 33 94 69 Example6 >10000 — 348 56 Example 7 2620 37 227 59 Example 8 921 36 33 58Example 9 792 40 7 81 Example 11 >10000 — 8 80

3. In Vivo Efficacy

The in vivo efficacy of 5-HT_(2C) agonists was assessed by the abilityof the compounds to induce three specific behaviours (5HT_(2C) Syndrome)in rats.

The 5-HT_(2c) syndrome is a rapid screening method to assess the in vivoefficacy of 5-HT_(2c) agonists through their ability to induce threespecific behaviours in rats. The animals were dosed with either apositive control (mCPP), test compound or vehicle, eithersub-cutaneously or p.o. The animals were observed on an open bench,typically 30, 60 and 180 minutes after dosing and the degree of syndromewas assessed over a two minute period on a scale of 0-3 depending on thepresence and severity of splayed limbs, hunched posture andretro-pulsion, the three specific behaviours which constitute thesyndrome. Data were analysed using Kruskal-Wallis Analysis of Variancefollowed with appropriate post-hoc tests. All statistical analysis wereconducted using Excel version 7.0 (Microsoft Corp.) and Statisticaversion 5.0 (Statsoft, Inc.).

The thus determined activity of Example 3 indicates that after a dose of20 mg/kg s.c. the compound maintains significant pharmacologicalefficacy for at least 180 minutes.

Synthetic Examples Example 1(RS)-1-(7-Chloro-2,3-dihydro-1H-pyrrolo[1,2-a]indol-9-yl)-2-propylaminehydrochloride

5-Chloroindole-3-carboxaldehyde

To stirred dimethylformamide (20 mL) at 0° C. was added dropwisephosphorus oxychloride (4.6 mL, 49 mmol). The mixture was stirred for 10min and a solution of 5-chloroindole (5.0 g, 33 mmol) indimethylformamide (5 mL) was added dropwise. The mixture was heated to40° C. for 45 min, cooled to room temperature and then treated with asolution of sodium hydroxide (5.9 g, 148 mmol) in water (20 mL). Themixture was heated to 50° C. for 10 min, cooled to room temperature,poured onto crushed ice (100 mL) and filtered. The filter cake wasrecrystallised (methanol) to give the product as a white solid (3.5 g,59%): mp 215-216° C.; Found: C, 60.13; H, 3.40; N, 7.75%. C₉H₆ClNOrequires: C, 60.19; H, 3.37; N, 7.79%.

5-Chloro-1-(3-chloropropyl)indole-3-carboxaldehyde

To a stirred mixture of powdered potassium hydroxide (85%, 2.6 g, 39mmol) in methyl sulfoxide (20 mL) was added dropwise a solution of5-chloroindole-3-carboxaldehyde (3.5 g, 19 mmol) in methyl sulfoxide (5mL). The mixture was stirred for 30 min and 1-bromo-3-chloropropane (2.9mL, 29 mmol) was added dropwise. The mixture was stirred for 1 h andpartitioned between ethyl acetate (3×40 mL) and water (100 mL). Thecombined organic extracts were washed (water, brine), dried (sodiurnsulfate) and concentrated in vacuo. The solid residue was recrystallised(2-propanol) to give the product as a white solid (4.1 g, 82%): mp107-108° C.; Found: C, 56.51; H, 4.26; N, 5.44%. C₁₂H₁₁Cl₂NO requires:C, 56.27; H, 4.33; N, 5.47%.

5-Chloro-1-(3-iodopropyl)indole-3-carboxaldehyde

A stirred solution of 5-chloro-1-(3-chloropropyl)indole-3-carboxaldehyde(3.8 g, 15 mmol) and sodium iodide (4.5 g, 30 mmol) in acetonitrile (50mL) under argon was heated under reflux for 18 h, cooled to roomtemperature and partitioned between ether (3×30 mL) and water (50 mL).The combined organic extracts were washed (aqueous sodium metabisulfitesolution, water, brine), dried (sodium sulfate) and concentrated invacuo to give the product as a yellow oil (5.0 g, 96%) which was usedimmediately.

7-Chloro-2,3-dihydro-1H-pyrrolo[1,2-a]indole-9-carboxaldehyde

To a stirred solution of5-chloro-1-(3-iodopropyl)indole-3-carboxaldehyde (5.0 g, 14 mmol) intoluene (75 mL) at reflux under argon was added dropwise over 2 h asolution of 1,1′-azobis(cyclohexanecarbonitrile) (3.5 g, 14 mmol) andtri-n-butyltin hydride (7.8 mL, 29 mmol) in toluene (75 mL). The mixturewas stirred for 3 h, cooled to room temperature, and potassiurn fluoride(3.5 g, 60 mmol) and water (15 mL) were added. The mixture was stirredfor 18 h and filtered through a pad of kieselguhr. The filter-cake waswashed (ethyl acetate) and the filtrate was concentrated in vacuo,purified by colurnn chromatography [SiO₂; ethyl acetate-hexane (9:1)]and recrystallised (methanol) to give the product as a white solid (1.1g, 36%): mp 179-180° C.; Found: C, 65.54; H, 4.61; N, 6.38%. C₁₂H₁₀ClNOrequires: C, 65.61; H, 4.59; N, 6.37%.

1-(7-Chloro-2,3-dihydro-1H-pyrrolo[1,2-a]indol-9-yl)-2-nitro-1-propene

A stirred solution of7-chloro-2,3-dihydro-1H-pyrrolo[1,2-a]indole-9-carboxaldehyde (1.0 g,4.6 mmol) and ammonium acetate (0.4 g, 5.2 mmol) in nitroethane (10 mL)was heated to 100° C. for 1 h, cooled to room temperature, diluted withmethanol (30 mL), cooled to 0° C., and filtered. The filter-cake wasrecrystallised (toluene) to give the product as yellow needles (0.58 g,46%): mp 162-1623° C.; Found: C, 60.68; H, 4.67; N, 9.98%. C₁₄H₁₃ClN₂O₂requires: C, 60.77; H, 4.73; N, 10.12%.

(RS)-1-(7-Chloro-2,3 -dihydro-1H-pyrrolo[1,2-a]indol-9-yl)-2-propylaminehydrochloride

To a stirred solution of lithium aluminium hydride (1.0 M in THF, 2.7mL, 2.7 mmol) in added THF (5 mL) under argon was added dropwise asolution of1-(7-chloro-2,3-dihydro-1H-pyrrolo[1,2-a]indol-9-yl)-2-nitro-1-propene(0.5 g, 1.8 mmol) in THF (10 mL). The mixture was heated under refluxfor 4 h and cooled to 0° C. To the mixture was added dropwise aqueouspotassium sodium tartrate solution (50 mL) and the mixture was stirredfor 30 min and filtered through kieselguhr. The filtrate was extractedwith dichloromethane (3×30 mL). The combined organic extracts werewashed (water, brine), dried (sodium sulfate), concentrated in vacuo,treated with ethereal hydrogen chloride (1.0 M, 2 mL, 2 mmol) andconcentrated in vacuo. The concentrate was recrystallised (2-propanol)to give the title compound as a white solid (0.23 g, 45%): mp 272-273°C.; Found: C, 57.86; H, 6.37; N, 9.41%. C₁₄H₁₇ClN₂.HCl. 0.25H₂Orequires: C, 58.03; H, 6.39; N, 9.67%.

Example 2(RS)-1-(6,7-Difluoro-2,3-dihydro-1H-pyrrolo[1,2-a]indol-9-yl)-2-propylaminehydrochloride

5,6-Difluoroindole-3-carboxaldehyde

5,6-Difluoroindole-3-carboxaldehyde was prepared from 5,6-difluoroindoleaccording to the method described in Example 1 to give 2.9 g (78%) ofthe product as a pale yellow solid: mp 236-238° C.; Found: C, 58.34; H,2.79; N, 7.27%. C₉H₅F₂NO.0.25H₂O requires: C, 58.23; H, 2.99; N, 7.55%.

5,6-Difluoro-1-(3-chloropropyl)indole-3-carboxaldehyde

5,6-Difluoro-1-(3-chloropropyl)indole-3-carboxaldehyde was prepared from5,6-difluoroindole-3-carboxaldehyde according to the method described inExample 1 to give the 2.9 g (78%) of the product as a yellow solid: mp111-113° C.; Found: C, 55.87; H, 3.94; N, 5.40%. C₁₂H₁₀ClF₂NO requires:C, 55.94; H, 3.91; N, 5.44%.

5,6-Difluoro-1-(3-iodopropyl)indole-3-carboxaldehyde

5,6-Difluoro-1-(3-iodopropyl)indole-3-carboxaldehyde was prepared from5,6-difluoro -1-(3-chloropropyl)indole-3-carboxaldehyde according to themethod described in Example 1 with the following modification: the crudeproduct was purified by column chromatography [SiO₂; hexane-ethylacetate (3:2)] to give the product as a yellow solid (2.7 g, 87%). Asample recrystallised from ethyl acetate-hexane gave mp 95-97° C.;Found: C, 41.42; H, 2.94; N, 3.99%. C₁₂H₁₀F₂INO requires: C, 41.28; H,2.89; N, 4.01%.

6,7-Difluoro-2,3-dihydro-1H-pyrrolo[1,2-a]indole-9-carboxaldehyde

6,7-Difluoro-2,3-dihydro-1H-pyrrolo[1,2-a]indole-9-carboxaldehyde wasprepared from 5,6-difluoro-1-(3-iodopropyl)indole-3-carboxaldehydeaccording to the method described in Example 1 with the followingmodification: the crude product was purified by column chromatography[SiO₂; hexane-ethyl acetate (1:1)] to give the product as a pale yellowsolid (1.1 g, 66%) which was used immediately without furtherpurification.

1-(6,7-Difluoro-2,3-dihydro-1H-pyrrolo[1,2-a]indol-9-yl)-2-nitro-1-propene

1-(6,7-Difluoro-2,3-dihydro-1H-pyrrolo[1,2-a]indol-9-yl)-2-nitro-1-propenewas prepared from6,7-difluoro-2,3-dihydro-1H-pyrrolo[1,2-a]indole-9-carboxaldehydeaccording to the method described in Example 1 with the followingmodifications: the reaction mixture was stirred at 100° C. for 1 h,cooled to room temperature and partitioned between ethyl acetate (3×30mL) and water. The combined organic extracts were washed (brine), dried(magnesium sulfate) and concentrated in vacuo to give the crude productwhich was purified by column chromatography [SiO₂; hexane-ethyl acetate(3:1)] to give the product as a yellow solid (0.9 g, 72%). A samplerecrystallised from methanol gave mp 156-8° C.; Found: C, 62.63; H,5.42; N, 9.30%. C₁₄H₁₂F₂N₂O₂.0.3C₆H₁₄ requires: C, 62.40; H, 5.37; N,9.21%.

(RS)-1-(6,7-Difluoro-2,3-dihydro-1H-pyrrolo[1,2-a]indol-9-yl)-2-propylaminehydrochloride

(RS)-1-(6,7-Difluoro-2,3-dihydro-1H-pyrrolo[1,2-a]indol-9-yl)-2-propylaminehydrochloride was prepared from1-(6,7-difluoro-2,3-dihydro-1H-pyrrolo[1,2-a]indol-9-yl)-2-nitro-1-propeneaccording to the method described in Example 1 with the followingmodifications: the reaction mixture was heated under reflux for 4 h,cooled to 0° C. and poured into aqueous potassium sodium tartratesolution (150 mL) and diethyl ether (100 mL). The mixture was stirredfor 30 min, filtered through celite® and the filtrate was extracted withethyl acetate (2×50 mL). The combined organic extracts were washed(brine), dried (magnesium sulfate), concentrated in vacuo, treated withethereal hydrogen chloride (1.0 M, 2 mL, 2 mmol) and concentrated invacuo. The residue was recrystallised (ethyl acetate, 2-propanol) togive the title compound as a white solid (0.55 g, 63%): mp 264-266° C.Found: C, 58.67; H, 6.09; N, 9.65%. C₁₄H₁₆F₂N₂.HCl requires: C, 58.64;H, 5.98; N, 9.76%.

Example 3(RS)-1-(7-Methoxy-2,3-dihydro-1H-pyrrolo[1,2-a]indol-9-yl)-2-propylaminefumarate

5-Methoxyindole-3-carboxaldehyde

5-Methoxyindole-3-carboxaldehyde was prepared from 5-methoxyindoleaccording to the method described in Example 1 to give 5.1 g (85%) ofthe product as a white solid: mp 179-180° C.; Found: C, 68.37; H, 5.15;N, 7.98%. C₁₀H₉NO₂ requires C, 68.56; H, 5.18; N, 7.99%.

1-(3-Chloropropyl)-5-methoxy-indole-3-carboxaldehyde

1-(3-Chloropropyl)-5-methoxy-3-carboxaldehyde was prepared from5-methoxyindole-3-carboxaldehyde according to the method described inExample 1 with the following modifications: the reaction mixture wasstirred for 18 h, poured into ice-water (100 mL) and filtered. Thefilter-cake was recrystallised [isopropyl ether, 2-propanol (1:1)] togive the product as a white, crystalline solid (4.6 g, 63%): mp 75-76°C.; NMR δ_(H) (400 MHz, CDCl₃) 2.29 (2H, quintet, J 6 Hz) 3.46 (2H, t, J6 Hz) 3.87 (3H, s) 4.36 (2H, t, J 6 Hz) 6.95(1H, dd, J 2.5, 9 Hz) 7.27(1H, d, J 9 Hz) 7.69(1H, s) 7.77(1H, d, J 2.5 Hz) 9.94 (1H, s).

1-(3-Iodopropyl)-5-methoxy-indole-3-carboxaldehyde

1-(3-Iodopropyl)-5-methoxy-indole-3-carboxaldehyde was prepared from1-(3-chloropropyl)-5-methoxy-indole-3-carboxaldehyde according to themethod described in Example 1 with the following modification: thereaction mixture was heated under reflux for 18 h, cooled to roomtemperature and partitioned between ether (3×30 mL) and water (50 mL).The combined organic extracts were washed (aqueous sodium metabisulfitesolution, water, brine), dried (sodium sulfate) and concentrated invacuo. The crude product was purified by column chromatography [SiO₂;heptane-ethyl acetate (3:1)] to give the product as a yellow oil (4.9 g,78%) which was used immediately.

7-Methoxy-2,3-dihydro-1H-pyrrolo[1,2-a]indole-9-carboxaldehyde

7-Methoxy-2,3-dihydro-1H-pyrrolo[1,2-a]indole-9-carboxaldehyde wasprepared from 1-(3-iodopropyl)-5-methoxy-indole-3-carboxaldehydeaccording to the method described in Example 1 to give 0.41 g (13%) ofthe product as a white solid: mp 151-152° C.; Found: C, 72.25; H, 6.10;N, 6.46%. C₁₃H₁₃NO₂ requires: C, 72.54; H, 6.09; N, 6.50%.

1-(7-Methoxy-2,3-dihydro-1H-pyrrolo[1,2-a]indol-9-yl)-2-nitro-1-propene

1-(7-Methoxy-2,3-dihydro-1H-pyrrolo[1,2-a]indol-9-yl)-2-nitro-1-propenewas prepared from7-methoxy-2,3-dihydro-1H-pyrrolo[1,2-a]indole-9-carboxaldehyde accordingto the method described in Example 1 with the following modification:the reaction mixture was heated to 100° C. for 1 h, cooled to roomtemperature and partitioned between ethyl acetate (2×20 mL) and water(30 mL). The combined organic extracts were washed (water, brine), dried(sodium sulfate), concentrated in vacuo and purified by columnchromatography [SiO₂; ethyl acetate-heptane (1:1)] to give the productas yellow needles (0.46 g, 91%): mp 143° C.; Found: C, 66.32; H, 5.89;N, 10.27%. C₁₅H₁₆N₂O₃ requires: C, 66.16; H, 5.92; N, 10.28%.

(RS)-1-(7-Methoxy-2,3-dihydro-1H-pyrrolo[1,2-a]indol-9-yl)-2-propylaminefumarate

(RS)-1-(7-Methoxy-2,3-dihydro-1H-pyrrolo[1,2-a]indol-9-yl)-2-propylaminefumarate was prepared from1-(7-methoxy-2,3-dihydro-1H-pyrrolo[1,2-a]indol-9-yl)-2-nitro-1-propeneaccording to hthe method described in Example 1 with the followingmodifications: the reaction mixture was heated under reflux for 4 h,cooled to 0° C. and aqueous potassium sodium tartrate solution (50 mL)was added slowly. The mixture was stirred for 30 min, filtered through apad of kieselguhr and the filtrate was extracted with dichloromethane(3×30 mL). The combined organic extracts were washed (water, brine),dried (sodium sulfate) and concentrated in vacuo. The concentrate wasdissolved in 2-propanol (1 mL) and added to a solution of fumaric acid(0.17 g, 1.5 mmol) in 2-propanol (20 mL) at 50° C. The solution wascooled to 0° C. and filtered. The filter-cake was washed (2-propanol,ether) and dried to give the title compound as a white solid (0.22 g,42%): mp 194-196° C.; Found: C, 63.27; H, 6.80; N, 7.69%. C₁₉H₂₄N₂O₅requires: C, 63.32; H, 6.71; N, 7.77%.

Example 4(RS)-1-(8-Chloro-2,3-dihydro-1H-pyrrolo[1,2-a]indol-9-yl)-2-propylaminehemifumarate

4-Chloroindole-3-carboxaldehyde

4-Chloroindole-3-carboxaldehyde was prepared from 4-chloroindoleaccording to the method described in Example 1 to give 7.8 g (100%) ofthe product which was used without further purification.

4-Chloro-1-(3-chloropropyl)indole-3-carboxaldehyde

4-Chloro-1-(3-chloropropyl)indole-3-carboxaldehyde was prepared from4-chloroindole-3-carboxaldehyde according to the method described inExample 1 to give 3.8 g (45%, from 4-chloroindole) of the product as awhite solid: mp 89° C.; Found: C, 56.16; H, 4.23; N, 5.40%. C₁₂H₁₁Cl₂NOrequires: C, 56.27; H, 4.33; N, 5.47%.

4-Chloro-1-(3-iodopropyl)indole-3-carboxaldehyde

4-Chloro-1-(3-iodopropyl)indole-3-carboxaldehyde was prepared from4-chloro-1-(3-chloropropyl)indole-3-carboxaldehyde according to themethod described in Example 1 to give 4.2 g (83%) of the product as ayellow solid which was used immediately without further purification.

8-Chloro-2,3-dihydro-1H-pyrrolo[1,2-a]indole-9-carboxaldehyde

8-Chloro-2,3 -dihydro-1H-pyrrolo[1,2-a]indole-9-carboxaldehyde wasprepared from 4-chloro-1-(3-iodopropyl)indole-3-carboxaldehyde accordingto the method described in Example 1 to give 1.0 g (39%) of the productas a white solid; mp 160-161° C.; Found: C, 65.70; H, 4.54; N, 6.34%.C₁₂H₁₀NClO requires: C, 65.61; H, 4.59; N, 6.37%.

1-(8-Chloro-2,3-dihydro-1H-pyrrolo[1,2-a]indol-9-yl)-2-nitro-1-propene

1-(8-Chloro-2,3-dihydro-1H-pyrrolo[1,2-a]indol-9-yl)-2-nitro-1-propenewas prepared from8-chloro-2,3-dihydro-1H-pyrrolo[1,2-a]indole-9-carboxaldehyde accordingto the method described in Example 3 to give 1.1 g (95%) of the productas yellow needles: mp 137-138° C.; Found: C, 60.68; H, 4.73; N, 9.95%.C₁₄H₁₃N₂ClO₂ requires: C, 60.77; H, 4.73; N, 10.12%.

(RS)-1-(8-Chloro-2,3-dihydro-1H-pyrrolo[1,2-a]indol-9-yl)-2-propylaminehemifumarate

(RS)-1-(8-Chloro-2,3-dihydro-1H-pyrrolo[1,2-a]indol-9-yl)-2-propylaminehemifumarate was prepared from1-(8-chloro-2,3-dihydro-1H-pyrrolo[1,2-a]indol-9-yl)-2-nitro-1-propeneaccording to the method described in Example 3 to give 0.71 g (53%) ofthe product as a white solid. A sample recrystallised from 2-propanolgave mp 207-208° C.; Found: C, 61.67; H, 6.31; N, 8.79%.C₁₄H₁₇N₂Cl.0.5C₄O₄.0.25H₂O requires: C, 61.73; H, 6.31; N, 9.00%.

Example 5(RS)-1-(7-Bromo-2,3-dihydro-1H-pyrrolo[1,2-a]indol-9-yl)-2-propylaminefumarate

5-Bromoindole-3-carboxaldehyde

5-Bromoindole-3-carboxaldehyde was prepared from 5-bromoindole accordingto the method described in Example 1 to give 5.1 g (89%) of the productas a beige solid which was used without further purification: IR ν_(max)(Nujol)/cm⁻¹ 3222, 2925, 2855, 1712, 1644, 1524, 1459, 1441, 1378, 1290,1129, 1096, 856, 799, 782, 728, 673, 609 and 573; NMR δ_(H) (400 MHz,CDCl₃) 6.31 (1H, dd, J 2, 8.5 Hz) 6.41 (1H, d, J 8.5 Hz) 7.13 (1H, d, J2 Hz) 7.26 (1H, s) 8.84 (1H, s) 11.21 (1H, s).

5-Bromo-1-(3-chloropropyl)indole-3-carboxaldehyde

5-Bromo-1-(3-chloropropyl)indole-3-carboxaldehyde was prepared from5-bromoindole-3-carboxaldehyde according to the method described inExample 1 with the following modification: the reaction mixture wasstirred for 18 h, poured into ice-water (200 mL) and filtered. Thefilter-cake was washed (water, heptane), dried and purified by columnchromatography (SiO₂; ethyl acetate) to give 4.6 g (77%) of the productas a white solid: IR ν_(max) (Nujol)/cm⁻¹ 2925, 2855, 1660, 1610, 1532,1469, 1402, 1378, 1302, 1171, 1195, 1035, 968, 818, 786, 722, 666, 622and 610; NMR δ_(H) (400 MHz, CDCl₃) 2.32 (2H, m) 3.48 (2H, t, J 6.5 Hz)4.41 (2H, t, J 6.5 Hz) 7.28 (1H, d, J 9 Hz) 7.44 (1H, dd, J 2, 8.5 Hz)7.76 (1H, s) 8.47 (1H, d, J 3 Hz) 9.98 (1H, s).

5-Bromo-1-(3-iodopropyl)indole-3-carboxaldehyde

5-Bromo-1-(3-iodopropyl)indole-3-carboxaldehyde was prepared from5-chloro-1-(3-chloropropyl)indole-3-carboxaldehyde according to themethod described in Example 1 to give 6.0 g (100%) of the product as ayellow oil which was immediately.

7-Bromo-2,3-dihydro-1H-pyrrolo[1,2-a]indole-9-carboxaldehyde

7-Bromo-2,3-dihydro-1H-pyrrolo[1,2-a]indole-9-carboxaldehyde wasprepared from 5-bromo-1-(3-iodopropyl)indole-3-carboxaldehyde accordingto the method described in Example 1 to give 1.2 g (32%) of the productas a white solid: mp 189-191° C.; IR ν_(max) (Nujol)/cm⁻¹ 2925, 2855,1651, 1606, 1534, 1452, 1442, 1397, 1377, 1360, 1314, 1288, 1245, 1050,1038, 802, 775, and 571; NMR δ_(H) (400 MHz, CDCl₃) 2.72 (2H, m) 3.25(2H, t, J 7.5 Hz) 4.08 (2H, t, J 7 Hz) 7.07 (1H, d, J 8.5 Hz) 7.29 (1H,d, J 8.5 Hz) 8.31 (1H, s) 9.90 (1H, s).

1-(7-Bromo-2,3-dihydro-1H-pyrrolo[1,2-a]indol-9-yl)-2-nitro-1-propene

1-(7-Bromo-2,3-dihydro-1H-pyrrolo[1,2-a]indol-9-yl)-2-nitro-1-propenewas prepared from7-bromo-2,3-dihydro-1H-pyrrolo[1,2-a]indole-9-carboxaldehyde accordingto the method described in Example 1 to give 1.1 g (81%) of the productas yellow needles: mp 173° C.; Found: C, 52.44; H, 4.10; N, 8.75%.C₁₄H₁₃N₂BrO requires: C, 52.36; H, 4.08; N, 8.72%.

(RS)-1-(7-Bromo-2,3-dihydro-1H-pyrrolo[1,2-a]indol-9-yl)-2-propylaminefumarate

(RS)-1-(7-Bromo-2,3-dihydro-1H-pyrrolo[1,2-a]indol-9-yl)-2-propylaminefumarate was prepared from1-(7-bromo-2,3-dihydro-1H-pyrrolo[1,2-a]indol-9-yl)-2-nitro-1-propeneaccording to the method described in Example 3 to give 0.38 g (60%) ofthe product as a white solid: mp 181-183° C.; IR ν_(max) (Nujol)/cm⁻¹2925, 2855, 1702, 1632, 1580, 1524, 1464, 1378, 1317, 1277, 1222, 1167,1100, 1049, 986, 897, 783 722, 652 and 564; NMR δ_(H) (400 MHz, DMSO-d₆)1.14 (3H, d, J 7 Hz) 2.56 (2H, m) 2.96 (3H, m) 3.79 (1H, m) 4.05 (2H, t,J 7 Hz) 6.46 (2H, s) 7.15 (1H, dd, J 2, 8.5 Hz) 7.27 (1H, d, J8.5 Hz)7.72 (1H, d, J 2 Hz).

Example 6(RS)-1-(7-Methyl-2,3-dihydro-1H-pyrrolo[1,2-a]indol-9-yl)-2-propylaminefumarate

5-Methylindole-3-carboxaldehyde

5-Methylindole-3-carboxaldehyde was prepared from 5-methylindoleaccording to the method described in Example 1 to give 2.06 (42%) of theproduct as a pink solid: mp 148-149° C.; IR ν_(max) (Nujol)/cm−1 3145,2924, 1639, 1523, 1450, 1133, 805 and 616; NMR δ_(H ()400 MHz, DMSO-d₆)2.41 (3H, s), 3.32 (3H, s), 7.08 (1H, d, J 6.7 Hz), 7.39 (1H, d, J 8.2Hz), 7.90 (1H, s), 8.22 (1H, s), 9.90 (1H, s) and 12.01 (1H, br. s);Found: C, 75.24; H, 5.67; N, 8.83%. C₁₀H₉NO requires: C, 75.45; H, 5.70;N, 8.97%.

1-(3-Chloropropyl)-5-methyl-indole-3-carboxaldehyde

1-(3-Chloropropyl)-5-methyl-indole-3-carboxaldehyde was prepared from5-methylindole-3-carboxaldehyde according to the method described inExample 1 to give 2.26 g (76%) of the product as an off-white solid: mp89-90° C.; IR ν_(max) (Nujol)/cm⁻¹ 2956, 1659, 1536, 1403, 1171, 820 and786; NMR δ_(H) (400 MHz, CDCl₃) 2.27-2.34 (2H, m), 2.47 (3H, s), 3.46(2H, t, J 6.2 Hz), 4.38 (2H, t, J 6.6 Hz), 7.16 (1H, d, J 10 Hz), 7.28(1H, d, J 8.4 Hz), 7.70 (1H, s), 8.12 (1H, s) and 9.97 (1H, s); Found:C, 66.12; H, 6.00; N, 5.88%. C₁₃H₁₄ClNO requires: C, 66.24; H, 5.99; N,5.94%.

1-(3-Iodopropyl)-5-methyl-indole-3-carboxaldehyde

1-(3-Iodopropyl)-5-methyl-indole-3-carboxaldehyde was prepared from1-(3-chloropropyl)-5-methyl-indole-3-carboxaldehyde according to themethod described in Example 1 to give the product as pink oil which wasused immediately without further purification.

7-Methyl-2,3-dihydro-1H-pyrrolo[1,2-a]indole-9-carboxaldehyde

7-Methyl-2,3-dihydro-1H-pyrrolo[1,2-a]indole-9-carboxaldehyde wasprepared from 1-(3-iodopropyl)-5-methyl-indole-3-carboxaldehydeaccording to the method described in Example 1 to give 0.74 g (40%) ofthe product as a white solid: mp 148-149° C.; IR ν_(max) (Nujol)/cm⁻¹2953, 1643, 1448, 1357, 1033 and 814; NMR δ_(H) (400 MHz, CDCl₃) 2.45(3H, s), 2.68-2.73 (2H, m), 3.27 (2H, t, J 7.7 Hz), 4.09 (2H, t, J 7.5Hz), 7.04 (1H, d, J 8.5 Hz), 7.13 (1H, d, J 8.6 Hz), 8.00 (1H, s) and9.96 (1H, s)

1-(7-Methyl-2,3-dihydro-1H-pyrrolo[1,2-a]indol-9-yl)-2-nitro-1-propene

1-(7-Methyl-2,3-dihydro-1H-pyrrolo[1,2-a]indol-9-yl)-2-nitro-1-propenewas prepared from7-methyl-2,3-dihydro-1H-pyrrolo[1,2-a]indole-9-carboxaldehyde accordingto the method described in Example 1 to give 0.73 g (68%) of the productas an orange solid: mp 138-139° C.; IR ν_(max) (Nujol)/cm⁻¹ 2925, 1634,1458, 1266, 1042, 977 and 799; NMR δ_(H) (400 MHz, CDCl₃) 2.42 (3H, s),2.46 (3H, s), 2.65-2.70 (2H, s), 3.10 (2H, t, J 7.0 Hz), 4.13 (2H, t, J7.0 Hz), 7.04 (1H, d, J 7.0 Hz), 7.15 (1H, d, J 8.0 Hz), 7.41 (1H, s)and 8.39 (1H, s); Found: C, 70.57; H, 6.76; N, 11.14%. C₁₅H₁₆N₂O₂requires: C, 70.29; H, 6.29; N, 10.92%.

(RS)-1-(7-Methyl-2,3-dihydro-1H-pyrrolo[1,2-a]indol-9-yl)-2-propylaminefumarate

(RS)-1-(7-Methyl-2,3-dihydro-1H-pyrrolo[1,2-a]indol-9-yl)-2-propylaminefumarate was prepared from1-(7-methyl-2,3-dihydro-1H-pyrrolo[1,2-a]indol-9-yl)-2-nitro-1-propeneaccording to the method described in Example 3 to give 0.61 g (71%) ofthe title compound as an off-white solid: mp darkens at 140° C., melts156-157° C.; IR ν_(max) (Nujol)/cm⁻¹ 2922, 1697, 1461, 1378, 979, 791and 652; NMR δ_(H) (400 MHz, DMSO-d₆) 1.25 (3H, d, J 6.5 Hz), 2.47 (3H,s), 2.63-2.67 (1H, m), 2.80-2.85 (1H, m), 2,94-3.08 (3H, m), 3.43-3.53(2H, m), 4.10 (2H, t, J 7.4 Hz), 6.52 (2H, s), 6.97 (1H, d, J 8.1 Hz),7.26 (1H, d, J 7.9 Hz) and 7.36 (1H, s); Found: C, 64.71; H, 7.30; N,8.12%. C₁₅H₂₀N₂.C₄H₄O₄.0.5H₂O requires: C, 64.57; H, 7.13; N, 7.93%.

Example 7(RS)-1-[6,7-(Methylenedioxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-9-yl]-2-propylaminefumarate

5,6-(Methylenedioxy)indole-3-carboxaldehyde

5,6-(Methylenedioxy)indole-3-carboxaldehyde was prepared from5,6-(methylenedioxy)indole according to the method described in Example1 to give 1.9 g (85%) of the product as a yellow solid: mp darkens anddecomposes over 180-190° C.; IR ν_(max) (nujol)/cm⁻¹ 3233, 2925, 1630,1472, 1294, 1177 and 937; NMR δ_(H) (400 MHz, DMSO-d₆) 6.01 (2H, s),7.03 (1H, s), 7.46 (1H, s), 8.08 (1H, s), 9.83 (1H, s) and 12.90 (1H,br. s).

1-(3-Chloropropyl)-5,6-(methylenedioxy)-indole-3 -carboxaldehyde

1-(3-Chloropropyl)-5,6-(methylenedioxy)-indole-3-carboxaldehyde wasprepared from 5,6-(methylenedioxy)indole-3-carboxyaldehyde according tothe method described in Example 1 to give 2.06 g (79%) of the product aslight-brown crystals: mp 108-109° C.; IR ν_(max) (nujol)/cm⁻¹ 2924,1656, 1534, 1250, 1163 and 939; NMR δ_(H) (400 MHz, CDCl₃) 2.27-2.30(2H, m), 3.47 (2H, t, J 6 Hz), 4.30 (2H, t, J 6 Hz), 5.98 (2H, s), 6.82(1H, s), 7.59 (1H, s), 7.70 (1H, s) and 9.90 (1H, s); Found: C, 58.92;H, 4.60; N, 5.23%. C₁₃H₁₂ClNO₃ requires: C, 58.77; H, 4.55; N, 5.27%.

1-(3-Iodopropyl)-5,6-(methylenedioxy)-indole-3 -carboxaldehyde

1-(3-Iodopropyl)-5,6-(methylenedioxy)-indole-3-carboxaldehyde wasprepared from1-(3-chloropropyl)-5,6-(methylenedioxy)-indole-3-carboxaldehydeaccording to the method described in Example 1 to give the product as abrown solid which was used immediately without further purification.

6,7-(Methylenedioxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indole-9-carboxaldehyde

This was prepared from1-(3-iodopropyl)-5,6-(methylenedioxy)-indole-3-carboxaldehyde accordingto the method described in Example 1 to give 1.0 g (75%) of the productas an off-white solid: mp 169-170° C.; IR ν_(max) (Nujol)/cm⁻¹ 2924,1639, 1645, 1244, 1133 and 944; NMR δ_(H) (400 MHz, CDCl₃) 2.68 (2H,quint, J 7.2 Hz), 7.20 (2H, t, J 7.2 Hz), 4.05 (2H, t, J 7.1 Hz), 5.95(2H, s), 6.70 (1H, s), 7.63 (1H, s) and 9.89 (1H, s).

1-[6,7-(Methylenedioxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-9-yl)-2-nitro-1-propene

1-[6,7-(Methylenedioxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-9-yl)-2-nitro-1-propenewas prepared from5,6-(methylenedioxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indole-9-carboxaldehydeaccording to the method described in Example 1 to give 0.76 g (62%) ofthe product as an orange solid: mp darkens over 202-210° C.; IR ν_(max)(Nujol)/cm⁻¹ 2924, 1635, 1458, 1246, 1197 and 861; NMR δ_(H) (400 MHz,CDCl₃) 2.40 (3H, s), 2.65 (2H, quint, J 7.4 Hz), 3.06 (2H, t, J 7.6 Hz),4.07 (2H, t, J 7.1 Hz), 5.95 (2H, s) 6.71 (1H, s), 7.00 (1H, s) and 8.30(1H, s); Found: C, 62.31; H, 5.25; N, 9.93%. C₁₅H₁₄N₂O₄ requires: C,62.93; H, 4.93; N, 9.78%.

(RS)-1-[(6,7-Methylenedioxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-9-yl)-2-propylaminefumarate

(RS)-1-[(6,7-Methylenedioxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-9-yl)-2-propylaminefumarate was prepared from1-[6,7-(methylenedioxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-9-yl)-2-nitro-1-propeneaccording to the method described in Example 3 to give 0.13 g (14%) ofthe title compound as an off-white solid: mp darkens over 135-140° C.;IR ν_(max) (Nujol)/cm⁻¹ 2923, 1632, 1466, 1235, 1039 and 652; NMR δ_(H)(400 MHz, DMSO-d₆) 1.12 (3H, d, J 6.6 Hz), 2.46-2.53 (1H, m), 2.63-2.69(1H, dd, J, 14.1, 8.4 Hz), 2.81-2.93 (3H, m), 3.26-3.39 (2H, m), 3.94(2H, t, J 7.0 Hz), 5.89 (2H, s), 6.40 (2H, s), 6.89 (1H, s) and 7.01(1H, s); Found: C, 58.48; H, 5.79; N, 7.25%. C₁₅H₁₈N₂O₂C₄H₄O₄.H₂Orequires: C, 58.16; H, 6.16; N, 7.14%.

Examples 8 and 9 Enantiomer 1 and Enantiomer 2 of1-(7-Methoxy-2,3-dihydro-1H-pyrrolo[1,2-a]indol-9-yl)-2-propylaminefumarate

(RS)-1-(7-Methoxy-2,3-dihydro-1H-pyrrolo[1,2-a]indol-9-yl)-2-(trifluoroacetamido)-propane

To a stirred solution of(RS)-1-(7-methoxy-2,3-dihydro-1H-pyrrolo[1,2-a]indol-9-yl)-2-propylamine(0.28 g, 1.1 mmol) in dichloromethane (10 mL) at 0° C. was addeddropwise trifluoroacetic anhydride (0.18 mL, 1.3 mmol). The mixture wasstirred for 1 h, concentrated in vacuo and purified by columnchromatography (SiO₂; ether) to afford the product (0.39 g, 100%) as abeige solid: mp 131-3° C.; IR ν_(max) (Nujol)/cm⁻¹ 3307, 3105, 2925,2855, 2727, 1784, 1695, 1501, 1377, 1249, 1228, 1194, 1171, 1041, 844,784 and 724; NMR δ_(H) (400 MHz, CDCl₃) 1.24 (3H, d, J 6.5 Hz) 2.60 (2H,m) 2.92 (4H, m) 3.85 (3H, s) 4.03 (2H, t, J 7 Hz) 4.36 (1H, m) 6.37 (1H,d, J 6.5 Hz, NH) 6.79 (1H, dd, J 2.5, 8.5 Hz) 6.96 (1H, d, J 3 Hz) 7.11(lH, d, J 9 Hz).

Enantiomer 1 and Enantiomer 2 of1-(7-Methoxy-2,3-dihydro-1H-pyrrolo[1,2-a]indol-9-yl)-2-(trifluoroacetamido)-propane

(RS)-(7-Methoxy-2,3-dihydro-1H-pyrrolo[1,2-a]indol-9-yl)-2-(trifluoroacetamido)-propane(0.10 g, 0.29 mmol) was dissolved in dichloromethane (500 μL) and halfof the resultant solution was repeat-loaded onto a Chiralcel OD column(300mm×4.6 mm) [10μL injections; 1.0 mL/min; hexane-2-propanol (90:10);220 nm] to afford, after removal of solvent, enantiomer 1 of(7-methoxy-2,3-dihydro-1H-pyrrolo[1,2-a]indol-9-yl)-2-(trifluoroacetamido)-propane(0.018 g, 36%) as an off-white solid; LC: [Chiralcel OD;hexane-2-propanol (90:10); 1.0 mL/min; 220 nm] 99.1% (11.59 min) and0.9% (15.90 min); [Supelcosil ABZ+; methanol-10 mM aqueous ammoniumacetate solution (80:20)] 96.4% (3.08 min); and (S orR)-(7-methoxy-2,3-dihydro-1H-pyrrolo[1,2-a]indol-9-yl)-2-(trifluoroacetamido)-propane(0.018 g, 36%, 92% e.e.) as a pale green solid; LC: [Chiralcel OD;hexane-2-propanol (90:10); 1.0 mL/min; 220 nm] 4.0% (11.47 min) and96.0% (15.76 min); [Supelcosil ABZ+; methanol-10 mM aqueous ammoniumacetate solution (80:20)] 94% (3.09 min).

Enantiomer 1 of1-(7-Methoxy-2,3-dihydro-1H-pyrrolo[1,2-a]indol-9-yl)-propylaminefumarate

To a solution of the first-eluting trifluoroacetamide enantiomer (0.018g, 0.05 mmol) in methanol (10 mL) was added potassium carbonate (0.02 g,0.14 mmol) and 5 drops of water, and the resultant suspension wasstirred for 18 h. The solvent was removed in vacuo and the residue wasdissolved in ethyl acetate, dried (magnesium sulfate), concentrated invacuo and purified by flash column chromatography [SiO₂; ethyl acetate→ethyl acetate-methanol-0.880 ammonia solution (90:8:2)] to afford acolourless oil (0.0055 g). The oil was dissolved in 2-propanol (0.1 mL)and added to a solution of fumaric acid (0.0039 g, 0.034 mmol) in2-propanol (1 mL) at 50° C. and the mixture was evaporated to a residualamount of solvent. Ether was added, and the mixture was filtered. Thefilter-cake was washed with cold ether to afford the product (0.0035 g,43%) as a white solid: LC: [Supelcosil ABZ+; methanol-10 mM aqueousanmmonium acetate solution (70:30)] 94% (1.95 min); LC (sample treatedwith excess trifluoroacetic anhydride): [Chiralcel OD; hexane-2-propanol(90:10); 1.0 mL/min; 220 nm]>99% (12.28 min); m/z (ES⁺) 308[(M+Na+MeCN)⁺, 5%], 245 (MH⁺, 7%) and 228 [(MH−NH₃)⁺, 100%].

Enantiomer 2 of1-(7-Methoxy-2,3-dihydro-1H-pyrrolo[1,2-a]indol-9-yl)-2-propylaminefumarate

enantiomer 2 of1-(7-Methoxy-2,3-dihydro-1H-pyrrolo[1,2-a]indol-9-yl)-2-propylaminefumarate was prepared from second-eluting trifluoroacetamide enantiomeraccording to the method described above to give 0.0018 g (25%) of theproduct as a white solid: LC: [Supelcosil ABZ+; methanol-10 mM aqueousammonium acetate solution (80:20)] 98% (1.69 min); LC (sample treatedwith excess trifluoroacetic anhydride): [Chiralcel OD; hexane-2-propanol(90:10); 1.0 mL/min; 220 nm] 1% (12.58 min) and 99% (17.07 min); m/z(ES₊) 245 (MH⁺, 5%) and 228 [(MH−NH₃)⁺, 100%].

Example 10(RS)-1-(7-Benzyloxy-2,3-dihydro-1H-pyrrolo[1,2-a]indol-9-yl)-2-propylaminefumarate

5-Benzyloxylindole-3-carboxaldehyde

5-Benzyloxylindole-3-carboxaldehyde was prepared from 5-benzyloxyindoleaccording to the method described in Example 1 to give the crude productas a pale-brown solid which was used immediately without furtherpurification.

5-Benzyloxy-1-(3-chloropropyl)indole-3-carboxaldehyde

5-Benzyloxy-1-(3-chloropropyl)indole-3-carboxaldehyde was prepared from5-benzyloxylindole-3-carboxaldehyde according to the method described inExample 1 to give 4.4 g (68% from 5-benzyloxyindole) of the product asbrown needles: mp 134-135° C.; IR ν_(max) (Nujol)/cm⁻¹ 2924, 1655, 1527,1228, 1036, 787 and 707; NMR δ_(H) (400 MHz, CDCl₃) 2.28 (2H, m),3.45-3.48 (2H, t, J 5.9 Hz), 4.37 (2H, t, J 6.5 Hz), 513 (2H, s), 7.05(1H, dd, J 9.1, 2.5 Hz), 7.28-7.48 (6H, m), 7.70 (1H, s), 7.91 (1H, d,J, 2.5 Hz) and 9.96 (1H, s); Found: C, 69.62; H, 5.58; N, 4.30%.C₁₉H₁₈ClNO₂ requires: C, 69.62; H, 5.53; N, 4.27%.

5-Benzyloxy-1-(3-iodopropyl)indole-3-carboxaldehyde

This was prepared from5-benzyloxy-1-(3-iodopropyl)indole-3-carboxaldehyde according to themethod described in Example 1 to give the product as an oil which wasused immediately without further purification.

7-Benzyloxy-2,3-dihydro-1H-pyrrolo[1,2-a]indole-9-carboxaldehyde

7-Benzyloxy-2,3-dihydro-1H-pyrrolo[1,2-a]indole-9-carboxaldehyde wasprepared from 5-benzyloxy-1-(3-chloropropyl)indole-3-carboxaldehydeaccording to the method described in Example 1 to give 1.55 g (40%) ofthe product as an off-white solid: mp 165-166° C.; IR ν_(max)(nujol)/cm⁻¹; 2925, 1640, 1458, 1228, 1136, 1033 and 723; NMR δ_(H) (400MHz, CDCl₃) 2.68-2.72 (2H, m), 3.27 (2H, t, J 7.5 Hz), 4.10 (2H, t, J7.6 Hz), 5.12 (2H, s), 6.92 (1H, d, J 2.6 Hz), 6.95-7.48 (6H, m), 7.82(1H, s) and 9.89 (1H, s); Found: C, 78.02; H, 5.92; N, 4.70%. C₁₉H₁₇NO₂requires: C, 78.33; H, 5.88; N, 4.81%.

1-(7-Benzyloxy-2,3-dihydro-1H-pyrrolo[1,2-a]indol-9-yl)-2-nitro-1-propene

1-(7-Benzyloxy-2,3-dihydro-1H-pyrrolo[1,2-a]indol-9-yl)-2-nitro-1-propenewas prepared from7-benzyloxy-2,3-dibydro-1H-pyrrolo[1,2-a]indole-9-carboxaldehydeaccording to the method described in Example 1 to give 0.71 g (74%) ofthe product as a dark brown solid: mp 146-147° C. (decomp); IR ν_(max)(Nujol)/cm⁻¹ 2925, 1626, 1465, 1267, 1208 and 855; NMR δ_(H) (400 MHz,CDCl₃) 2.37 (3H, s), 2.67-2.70 (2H, m), 3.09 (2H, t, J 7.1 Hz), 4.12(2H, t, J 7.1 Hz), 5.11 (2H, s), 6.95 (1H, dd, J 8.7, 2.5 Hz), 7.13-7.47(7H, m) and 8.35 (1H, s); Found: C, 72.17; H, 5.77; N, 7.95%. C₂₁H₂₀N₂O₃requires: C, 72.40; H, 5.79; N, 8.04%.

(RS)-1-(7-Benzyloxy-2,3-dibydro-1H-pyrrolo[1,2-a]indol-9-yl)-2-propylamine fumarate

This was prepared from1-(7-benzyloxy-2,3-dihydro-1H-pyrrolo[1,2-a]indol-9-yl)-2-nitro-1-propeneaccording to the method described in Example 3 to give 0.17g (18%) ofthe title compound as an off-white solid: mp darkens at 180° C., meltsover 188-198° C.; IR ν_(max) (Nujol)/cm⁻¹ 2923, 1626, 1464, 1222, 736and 650; NMR δ_(H) (400 MHz, DMSO-d₆) 1.13 (3H, d, J 6.6 Hz), 2.50-2.56(2H, m), 2.68-2.74 (1H, m), 2.87-2.96 (3H, m), 3.33-3.39 (1H, m), 3.99(2H, t, J 7.5 Hz), 5.09 (2H, s), 6.43 (2H, s), 6.74-677 (1H, dd, J 8.6,2.5 Hz) and 7.15-7.48 (7H, m); Found: C, 67.84; H, 6.37; N, 6.30%.C₂₁H₂₄N₂O.C₄H₄O₄0.5H₂O requires: C, 67.40; H, 6.56; N, 6.29%.

Example 11(RS)-1-(7-Methylthio-2,3-dihydro-1H-pyrrolo[1,2-a]indol-9-yl)-2-propylaminefumarate

5-Methylthioindole-3-carboxaldehyde

5-Methylthioindole-3-carboxaldehyde was prepared from 5-methylthioindole(Heterocycles, 1992, 34, 1169-1175) according to the method described inExample 1 to give 1.85 g (86%) of the product as a white solid: mp182-183° C.; IR ν_(max) (Nujol)/cm⁻¹ 3172, 2926, 2807, 1632, 1440, 1130and 972; NMR δ_(H) (400 MHz, DMSO-d₆) 2.50 (3H, s), 7.24 (1H, dd, J11.4, 2.8 Hz), 7.50 (1H, d, J, 11.5 Hz), 7.96 (1H, s), 8.28 (1H, s) and9.92 (1H, s).

1-(3-Chloropropyl)-5-methylthio-indole-3-carboxaldehyde

1-(3-Chloropropyl)-5-methylthio-indole-3-carboxaldehyde wa s pr eparedfrom 5-methylthioindole-3-carboxaldehyde according to the methoddescribed in Example 1 to give 2.36 g (94%) of the product as apale-yellow solid: mp 64-65° C.; IR ν_(max) (Nujol)/cm⁻¹ 2924, 2809,1656, 1534, 1399, 1172, 1027, 813 and 786; NMR δ_(H) (400 MHz, CDCl₃)2.27-2.33 (2H, m), 2.54 (3H, s), 3.46 (2H, t, J 5.7 Hz), 4.38 (2H, t, J6.5 Hz), 7.29 (2H, s), 7.71 (1H, s), 8.22 (1H, s) and 9.96 (1H, s).

1-(3-Iodopropyl)-5-methylthio-indole-3-carboxaldehyde

1-(3-Iodopropyl)-5-methylthio-indole-3-carboxaldehyde was prepared from1-(3-chloropropyl)-5 -methylthio-indole-3-carboxaldehyde according tothe method described in Example 1 to give the product as a pale-brownoil which was used immediately without further purification.

7-Methylthio-2,3-dihydro-1H-pyrrolo[1,2-a]indole-9-carboxaldehyde

7-Methylthio-2,3-dihydro-1H-pyrrolo[1,2-a]indole-9-carboxaldehyde wasprepared from 1-(3-iodopropyl)-5-methylthio-indole-3-carboxaldehydeaccording to the method described in Example 1 to give 0.80 g (40%) ofthe product as a pale-yellow solid: mp 140-141° C.; IR ν_(max)(Nujol)/cm⁻¹ 2924, 2724, 1639, 1465, 1029 and 820; NMR δ_(H) (400 MHz,CDCl₃) 2.53 (3H, s), 2.68-2.76 (2H, m), 3.28 (2H, t, J 7.5), 4.12 (2H,t, J 7.1 Hz), 7.14-7.22 (2H, m), 8.12 (1H, s) and 9.90 (1H, s).

1-(7-Methylthio-2,3-dihydro-1H-pyrrolo[1,2-a]indol-9-yl)-2-nitro-1-propene

1-(7-Methylthio-2,3-dihydro-1H-pyrrolo[1,2-a]indol-9-yl)-2-nitro-1-propenewas prepared from7-methylthio-2,3-dihydro-1H-pyrrolo[1,2-a]indole-9-carboxaldehydeaccording to the method described in Example 1 to give 0.60 g (80%) ofthe product as an orange solid: mp 135-136° C.; IR ν_(max) (Nujol)/cm⁻¹2924, 1636, 1475, 1277, 979 and 800; NMR δ_(H) (400 MHz, CDCl₃) 2.41(3H, s), 2.52 (3H, s), 2.66-2.70 (2H, m), 3.10 (2H, t, J 7.2 Hz), 4.14(2H, t, J 7.1 Hz), 7.17-7.23 (2H, m), 7.54 (1H, s) and 8.35 (1H, s).

(RS)-1-(7-Methylthio-2,3-dihydro-1H-pyrrolo[1,2-a]indol-9-yl)-2-propylaminefumarate

(RS)-1-(7-Methylthio-2,3-dihydro-1H-pyrrolo[1,2-a]indol-9-yl)-2-propylaminefumarate was prepared from1-(7-methylthio-2,3-dihydro-1H-pyrrolo[1,2-a]indol-9-yl)-2-nitro-1-propeneaccording to the method described in Example 3 to give 0.23 g (30%) ofthe title compound as pale-yellow crystals: mp 204-206° C. (dec.); IRν_(max) (Nujol)/cm⁻¹ 3052, 2924, 1612, 1463, 1310, 992 and 788; NMRδ_(H) (400 MHz, DMSO-d₆) 1.14 (3H, d, J 6.1 Hz), 2.46 (3H, s), 2.50-2.55(2H, m), 2.71-2.76 (1H, m), 2.89-2.99 (3H, m), 3.34-3.36 (1H, m), 4.02(2H, t, J 7.1 Hz), 6.43 (2H, s), 7.04 (1H, dd, J 8.4, 1.9 Hz), 7.24 (1H,d, J, 8.1 Hz) and 7.50 (1H, d, J 1.4 Hz).

Example 12 (RS)N-(2-Methylpropyl)-1-[(7-methoxy-2,3-dihydro-1H-pyrrolo[1,2-a]indol-9-yl)]-2-propylaminehydrochloride

A mixture of(RS)-(7-methoxy-2,3-dihydro-1H-pyrrolo[1,2-a]indol-9-yl)-2-propylamine(0.030 g, 0.12 mmol), 3-methylpropanal (0.021 mL, 0.24 mmol) andmethanol (1 mL) was shaken for 3 h. To the mixture was added AmberliteIRA-400 borohydride resin (2.5 mmol/g —BH₄, 0.12 g, 0.3 mmol) and themixture was shaken for 18 h. To the mixture was added PS-benzaldehyde(2.5 mmol/g —CHO, 0.12 g, 0.3 mmol) and the mixture was shaken for 18 hand filtered. The filter-cake was washed with dichloromethane (2×1 mL)and methanol (2×1 mL) and the filtrate was concentrated in vacuo. Theconcentrate was dissolved in dichloromethane (2 mL) and Amberlyst-15(0.5 g) was added. The mixture was shaken for 1 h and filtered. Thefilter-cake was washed with dichloromethane (2×1 mL) and methanol (2×1mL), suspended in methanolic ammonia solution (2 M, 1 mL, 2 mmol),shaken for 1 h, and filtered. The filter-cake was washed(dichloromethane) and the filtrate was concentrated in vacuo. Theconcentrate was treated with ethereal hydrogen chloride solution (1 M, 1mL, 1 mmol) and concentrated in vacuo to give the product as a beigesolid (0.02 g, 49%): mp 178-181° C.; NMR δ_(H) (400 MHz, DMSO-d₆) 1.01(6H, m) 1.17 (3H, d, J 6.5 Hz) 2.56 (2H, m) 2.77 (1H, m) 2.77 (1H, m)2.86 (1H, m) 2.93 (2H, m) 3.22 (1H, m) 3.39 (1H, m) 3.51 (1H, m) 3.78(3H, s) 4.02 (2H, t, J 7 Hz) 6.71 (1H, dd, J 2.5, 8.5 Hz) 7.11 )1H, s)7.19 (1H, d, J 8.5 Hz).

Example 13 (RS)N-(Cyclopropylmethyl)-1-[(7-methoxy-2,3-dihydro-1H-pyrrolo[1,2-a]indol-9-yl)]-2-propylaminehydrochloride

(RS)N-(Cyclopropylmethyl)-1-[(7-methoxy-2,3-dihydro-1H-pyrrolo[1,2-a]indol-9-yl)]-2-propylaminehydrochloride was prepared from(RS)-(7-methoxy-2,3-dihydro-1H-pyrrolo[1,2-a]indol-9-yl)-2-propylamineand cyclopropylcarboxaldehyde according to the method described inExample 12 to give 0.024 g (54%) of the product as a beige solid: mp149-151° C.; NMR δ_(H) (400 MHz, DMSO-d₆) 0.41 (2H, dd, J 5, 9 Hz) 0.62(2H, d, J 9 Hz) 1.15 (3H, d, J 6.5 Hz) 2.56 (2H, m) 2.73 (1H, dd, J10.5, 14 Hz) 2.93 (6H, m) 3.78 (3H, s) 4.02 (2H, t, J 7 Hz) 6.71 (1H,dd, J 2.5 9 Hz) 7.07 (1H, d, J 2.5 Hz) 7.19 (1H, d, J 9 Hz).

Example 14 (RS)N-(Cyclohexylmethyl)-1-[(7-methoxy-2,3-dihydro-1H-pyrrolo[1,2-a]indol-9-yl)]-2-propylaminehydrochloride

(RS)N-(Cyclohexylmethyl)-1-[(7-methoxy-2,3-dihydro-1H-pyrrolo[1,2-a]indol-9-yl)]-2-propylaminehydrochloride was prepared from(RS)-(7-methoxy-2,3-dihydro-1H-pyrrolo[1,2-a]indol-9-yl)-2-propylamineand cyclohexylcarboxaldehyde according to the method described inExample 12 to give 0.023 g (50%) of the product as a beige solid: mp210-3° C.; NMR δ_(H) (400 MHz, DMSO-d₆) 1.01 (2H, m) 1.17 (3H, d, J 6.5Hz) 1.22 (3H, m) 1.73 (6H, m) 2.55 (2H, m) 2.77 (1H, m) 2.84 (2H, m)2.93 (2H, m) 3.24 (1H, m) 3.39 (1H, m) 3.78 (3H, s) 4.02 (2H, t, J 7 Hz)6.70 (1H, dd J 2.5, 8.5 Hz) 7.13 (1H, d, J 2.5 Hz) 7.18 (1H, d, J 8.5Hz).

Example 15 (RS)N-(2,2-Dimethylpropyl)-1-[(7-methoxy-2,3-dihydro-1H-pyrrolo[1,2-a]indol-9-yl)]-2-propylaminehydrochloride

(RS)N-(2,2-Dimethylpropyl)-1-[(7-methoxy-2,3-dihydro-1H-pyrrolo[1,2-a]indol-9-yl)]-2-propylaminehydrochloride was prepared from from(RS)-(7-methoxy-2,3-dihydro-1H-pyrrolo[1,2-a]indol-9-yl)-2-propylamineand 2,2-dimethylpropionaldehyde according to the method described inExample 12 to give 0.030 g (70%) of the product as a beige solid: mp226-228° C.; NMR δ_(H) (400 MHz, DMSO-d₆) 1.07 (9H, s) 1.17 (3H, d, J6.5 Hz) 2.56 (2H, m) 2.65 (2H, m) 2.80 (1H, dd, J 11.5, 13.5 Hz) 2.89(2H, t, J 6.5 Hz) 2.94 (1H, m) 3.25 (1H, m) 3.79 (3H, s) 4.02 (2H, t, J7 Hz) 6.71 (1H, dd, J 2.5 8.5 Hz) 7.17 (1H, s) 7.20 (1H, d, J 8.5 Hz).

Example 16 (RS)N-(3-Methylbutyl)-1-(7-methoxy-2,3-dihydro-1H-pyrrolo[1,2-a]indol-9-yl)]-2-propylaminehydrochloride

(RS)N-(3-Methylbutyl)-1-(7-methoxy-2,3-dihydro-1H-pyrrolo[1,2-a]indol-9-yl)]-2-propylaminehydrochloride was prepared from from(RS)-(7-methoxy-2,3-dihydro-1H-pyrrolo[1,2-a]indol-9-yl)-2-propylamineand 3-methylbutyraldehyde according to the method described in Example12 to give 0.016 g (38%) of the product as a beige solid: mp 118-121°C.; NMR δ_(H) (400 MHz, DMSO-d₆) 0.92 (6H, d, J 14.5 Hz) 1.17 (3H, d, J6.5 Hz) 1.55 (2H, m) 1.67 (2H, m) 2.55 (2H, m) 2.74 (1H, dd, J 10, 14Hz) 2.94 (2H, m) 2.97 (2H, m) 3.19 (1H, dd, J, 4, 14 Hz) 3.78 (3H, s)4.02 (2H, t, J 7 Hz) 6.71 (1H, dd J 2.5, 8.5 Hz) 7.08 (1H, d, J 2.5 Hz)7.19 (1H, d, J 8.5 Hz).

Example 17(RS)-1-(2-Methoxy-6,7,8,9-tetrahydro-pyrido[1,2-a]indol-10-yl)-2-propylaminefumarate

5-Methoxyindole-3-carboxaldehyde

To stirred dimethylformamide is added dropwise phosphorus oxychloride.The mixture is stirred for 10 min and a solution of 5-methoxyindole indimethylformamide is added dropwise. The mixture is heated to 40° C. for45 min, cooled to room temperature and then treated with a solution ofsodium hydroxide in water. The mixture is heated to 50° C. for 10 min,cooled to room temperature, poured onto crushed ice and filtered. Thefilter cake is recrystallised (methanol) to give the product as a whitesolid.

5-Methoxy-1-(4-chlorobutyl)indole-3-carboxaldehyde

To a stirred mixture of powdered potassium hydroxide in methyl sulfoxideis added dropwise a solution of 5-methoxyindole-3-carboxaldehyde inmethyl sulfoxide. The mixture is stirred for 30 min and1-bromo-4-chlorobutane is added dropwise. The mixture is stirred for 1 hand partitioned between ethyl acetate and water. The combined organicextracts are washed (water, brine), dried (sodium sulfate) andconcentrated in vacuo to give the product.

5-Methoxy-1-(4-iodobutyl)indole-3-carboxaldehyde

A stirred solution of 5-methoxy-1-(4-chlorobutyl)indole-3-carboxaldehydeand sodium iodide in acetonitrile under argon is heated under reflux for18 h, cooled to room temperature and partitioned between ether andwater. The combined organic extracts are washed (aqueous sodiummetabisulfite solution, water, brine), dried (sodium sulfate) andconcentrated in vacuo to give the product.

2-Methoxy-6,7,8,9-tetrahydro-pyrido[1,2-a]indole-10-carboxaldehyde

To a stirred solution of5-methoxy-1-(4-iodobutyl)indole-3-carboxaldehyde in toluene at refluxunder argon is added dropwise over 2 h a solution of1,1′-azobis(cyclohexanecarbonitrile) and tri-n-butyltin hydride intoluene. The mixture is stirred for 3 h, cooled to room temperature, andpotassium fluoride and water are added. The mixture is stirred for 18 hand filtered through a pad of kieselguhr. The filter-cake is washed(ethyl acetate) and the filtrate is concentrated in vacuo and purifiedby column chromatography to give the product.

1-(2-Methoxy-6,7,8,9-tetrahydro-pyrido[1,2-a]indol-10-yl)-2-nitro-1-propene

A stirred solution of2-methoxy-6,7,8,9-tetrahydro-pyrido[1,2-a]indole-10-carboxaldehyde andammonium acetate in nitroethane is heated to 100° C. for 1 h, cooled toroom temperature and partitioned between ethyl acetate and water. Thecombined organic extracts are washed (water, brine), dried (sodiumsulfate) and concentrated in vacuo to give the product.

(RS)-1-(2-Methoxy-6,7,8,9-Tetrahydro-pyrido[1,2-a]indol-10-yl)-2-propylamine fumarate

To a stirred solution of lithium aluminium hydride in tetrahydrofuranunder argon is added dropwise a solution of1-(2-methoxy-6,7,8,9-tetrahydro-1H-pyrido[1,2-a]indol-10-yl)-2-nitro-1-propenein tetrahydrofuran. The mixture is heated under reflux for 4 h andcooled to 0° C. To the mixture is added dropwise aqueous potassiumsodium tartrate solution and the mixture is stirred for 30 min andfiltered through kieselguhr. The filtrate is extracted withdichloromethane. The combined organic extracts are washed (water,brine), dried (sodium sulfate), concentrated in vacuo, dissolved in hot2-propanol and added dropwise to a stirred solution of fumaric acid in2-propanol at 50° C. The mixture is cooled to 0° C. and filtered. Thefilter-cake is washed (2-propanol, ether) and dried to give the product.

Example 18(RS)-1-(2-Methoxy-7,8,9,10-tetrahydro-6H-azepino[1,2-a]indol-11-yl)-2-propylaminefumarate

5-Methoxyindole-3-carboxaldehyde

To stirred dimethylformamide is added dropwise phosphorus oxychloride.The mixture is stirred for 10 min and a solution of 5-methoxyindole indimethylformamide is added dropwise. The mixture is heated to 40° C. for45 min, cooled to room temperature and then treated with a solution ofsodium hydroxide in water. The mixture is heated to 50° C. for 10 min,cooled to room temperature, poured onto crushed ice and filtered. Thefilter cake is recrystallised (methanol) to give the product as a whitesolid.

5-Methoxy-1-(5-chloropentyl)indole-3-carboxaldehyde

To a stirred mixture of powdered potassium hydroxide in methyl sulfoxideis added dropwise a solution of 5-methoxyindole-3-carboxaldehyde inmethyl sulfoxide. The mixture is stirred for 30 min and1-bromo-5-chloropentane is added dropwise. The mixture is stirred for 1h and partitioned between ethyl acetate and water. The combined organicextracts are washed (water, brine), dried (sodium sulfate) andconcentrated in vacuo to give the product.

5-Methoxy-1-(5-iodopentyl)indole-3-carboxaldehyde

A stirred solution of5-methoxy-1-(5-chloropentyl)indole-3-carboxaldehyde and sodium iodide inacetonitrile under argon is heated under reflux for 18 h, cooled to roomtemperature and partitioned between ether and water. The combinedorganic extracts are washed (aqueous sodium metabisulfite solution,water, brine), dried (sodium sulfate) and concentrated in vacuo to givethe product.

2-Methoxy-7,8,9,10-tetrahydro-6H-azepino[1,2-a]indole-11-carboxaldehyde

To a stirred solution of5-methoxy-1-(5-iodopentyl)indole-3-carboxaldehyde in toluene at refluxunder argon is added dropwise over 2 h a solution of1,1′-azobis(cyclohexanecarbonitrile) and tri-n-butyltin hydride intoluene. The mixture is stirred for 3 h, cooled to room temperature, andpotassium fluoride and water are added. The mixture is stirred for 18 hand filtered through a pad of kieselguhr. The filter-cake is washed(ethyl acetate) and the filtrate is concentrated in vacuo and purifiedby column chromatography to give the product.

1-(2-Methoxy-7,8,9,10-tetrahydro-6H-azepino[1,2-a]indol11-yl)-2-nitro-1-propene

A stirred solution of2-methoxy-7,8,9,10-tetrahydro-6H-azepino[1,2-a]indole-11-carboxaldehydeand ammonium acetate in nitroethane is heated to 100° C. for 1 h, cooledto room temperature and partitioned between ethyl acetate and water. Thecombined organic extracts are washed (water, brine), dried (sodiumsulfate) and concentrated in vacuo to give the product.

(RS)-1-(2-Methoxy-7,8,9,10-tetrahydro-6H-azepino[1,2-a]indol-11-yl)-2-propylaminefumarate

To a stirred solution of lithium aluminium hydride in tetrahydrofuranunder argon is added dropwise a solution of1-(2-methoxy-7,8,9,10-tetrahydro-6H-azepino[1,2-a]indol-11-yl)-2-nitro-1-propenein tetrahydrofuran. The mixture is heated under reflux for 4 h andcooled to 0° C. To the mixture is added dropwise aqueous potassiumsodium tartrate solution and the mixture is stirred for 30 min andfiltered through kieselguhr. The filtrate is extracted withdichloromethane. The combined organic extracts are washed (water,brine), dried (sodium sulfate), concentrated in vacuo, dissolved in hot2-propanol and added dropwise to a stirred solution of fumaric acid in2-propanol at 50° C. The mixture is cooled to 0° C. and filtered. Thefilter-cake is washed (2-propanol, ether) and dried to give the product.

What is claimed is:
 1. A chemical compound of formula (I):

wherein: n is 1, 2 or 3; R₁ and R₂ are independently selected fromhydrogen and alkyl; R₃is alkyl; R₄ to R₇ are independently selected fromhydrogen, halogen, hydroxy, alkyl, aryl, alkoxy, aryloxy, alkylthio,arylthio, alkylsulfoxyl, alkylsulfonyl, arylsulfoxyl, arylsulfonyl,amino, monoalkylamino, dialkylamino, nitro, cyano, carboxaldehyde,alkylcarbonyl, arylcarbonyl, aminocarbonyl, monoalkylaminocarbonyl,dialkylaminocarbonyl, alkoxycarbonylamino, aminocarbonyloxy,monoalkylaminocarbonyloxy, dialkylaminocarbonyloxy,monoalkylaminocarbonylamino and dialkylaminocarbonylamino, or R₅ and R₆together form a carbocyclic or heterocyclic ring, or pharmaceuticallyacceptable salts thereof.
 2. A compound according to claim 1 whereinn=1.
 3. A compound according to claim 1 wherein R₁ and R₂ are hydrogen.4. A compound according to claim 1 wherein R₁ is hydrogen and R₂ isalkyl.
 5. A compound according to claim 1 wherein R₁ is hydrogen and R₂is arylalkyl.
 6. A compound according to claim 1 wherein R₃ is methyl.7. A compound according to claim 1 wherein R₄ to R₇ are selected thegroup consisting of hydrogen, halogen, hydroxy, alkyl, aryl, alkoxy,aryloxy, alkylthio, alkylsulfoxyl and alkylsulfonyl.
 8. A compoundaccording to claim 1 wherein R₄ is hydrogen or halogen.
 9. A claimaccording to claim 1 wherein R₅ is other than hydrogen.
 10. A compoundaccording to claim 1 wherein R₅ is selected from halogen, alkyl, alkoxyand alkylthio.
 11. A compound according to claim 1 wherein R₆ is otherthan hydrogen.
 12. A compound according to claim 1 wherein R₆ isselected from hydrogen and halogen.
 13. A compound according to claim 1wherein R₅ and R₆ together form an O, S or N containing heterocyclicring.
 14. A compound according to claim 13 wherein said ring is a 5-or6-membered ring.
 15. A compound according to any claim 1 wherein R₇ ishydrogen.
 16. A compound according to claim 1 wherein two or three ofR₄, R₅, R₆ and R₇ are hydrogen.
 17. A compound according to claim 1wherein the compounds of formula (I) are selected the group consistingof 1-(7-chloro-2,3-dihydro-1H-pyrrolo[1,2-a]indol-9-yl)-2-propylamine,1-(6,7-difluoro-2,3-dihydro-1H-pyrrolo[1,2-a]indol-9-yl)-2-propylamine,1-(7-bromo-2,3-dihydro-1H-pyrrolo[1,2-a]indol-9-yl)-2-propylamine,1-(7-methoxy-2,3-dihydro-1H-pyrrolo[1,2-a]indol-9-yl)-2-propylamine and1-(7-methylthio-2,3-dihydro-1H-pyrrolo[1,2-a]indol-9-yl)-2-propylamine.18. A compound according to claim 1 which is the (S)-enantiomer thereof.19. A method of treatment of disorders of the central nervous system;damage to the central nervous system; cardiovascular disorders;gastrointestinal disorders; diabetes insipidus, and sleep apneacomprising administering to a patient in need of such treatment aneffective dose of a compound of formula (I) as set out in claim
 1. 20. Amethod according to claim 19 wherein the disorders of the centralnervous system are selected the group consisting of depression, atypicaldepression, bipolar disorders, anxiety disorders, obsessive-compulsivedisorders, social phobias or panic states, sleep disorders, sexualdysfunction, psychoses, schizophrenia, migraine and other conditionsassociated with cephalic pain or other pain, raised intracranialpressure, epilepsy, personality disorders, age-related behaviouraldisorders, behavioural disorders associated with dementia, organicmental disorders, mental disorders in childhood, aggressivity,age-related memory disorders, chronic fatigue syndrome, drug and alcoholaddiction, obesity, bulimia, anorexia nervosa and premenstrual tension.21. A method according to claim 20 wherein the damage to the centralnervous system is by trauma, stroke, neurodegenerative diseases or toxicor infective CNS diseases.
 22. A method according to claim 21 whereinsaid toxic or infective CNS disease is encephalitis or meningitis.
 23. Amethod according to claim 19 wherein the cardiovascular disorder isthrombosis.
 24. A method according to claim 19 wherein thegastrointestinal disorder is dysfunction of gastrointestinal motility.25. A method according to claim 19 wherein said medicament is for thetreatment of obesity.
 26. A method according to claim 19 wherein saidtreatment is prophylactic treatment.
 27. A pharmaceutical compositioncomprising a compound of formula (I) as set out in claim 1 incombination with a pharmaceutically acceptable carrier or excipient.